Ultrasound cardiac stimulator

ABSTRACT

An ultrasound cardiac stimulation system comprising: a spatially selective ultrasound source comprising at least one ultrasound transducer located outside the circulatory system; and a controller; where the controller generates an electrical response in the heart by directing the ultrasound source to transmit a high enough power level of ultrasound to one or more locations in the heart.

RELATED APPLICATIONS

The present application is a U.S. national application of PCTApplication No. PCT/IL03/00134, filed on Feb. 19, 2003.

FIELD OF THE INVENTION

The present invention is related to the field of cardiac diagnosis andtherapy.

BACKGROUND OF THE INVENTION

The myocardium is susceptible to mechanical stimulation: case reportshave detailed incidents of cardiac arrest due to a ball or a fisthitting the person's thorax. Physiological studies have reportedinitiation of an action potential due to a mechanical stimulation suchas tapping of the epicardium [Avitall, B., Levine, H. J., Naimi, S.,Donahue, R. P., Pauker, S. G., and Adam, D. R., “Local effects ofelectrical and mechanical stimulation on the recovery properties ofcanine ventricle,” Am. J. Cardiology 50, 263-270 (1982)], or due tostretch. Separately, high energy ultrasound pulses have been reported toshatter kidney stones, while also affecting inner cellular structuresand membrane properties. In particular, it has been reported thatultrasound pulses increase membrane permeability and specific ion flow.Ultrasound transducers attached to cardiac catheters have been used toinduce electrical activity locally in the heart, for diagnosticpurposes. External ultrasound transducers used for imaging have alsobeen observed to induce action potentials in the heart, inadvertently,especially when contrast agents containing small bubbles are injectedinto the bloodstream. Because of the danger of inducing actionpotentials in the heart in an uncontrolled way, great care is takenduring ultrasound imaging of the heart not to induce action potentials.

Direct electrical stimulation of the heart is done for cardiac pacing,usually via electrodes implanted during surgery. Electrical stimulationis also used to measure cardiac response, as a diagnostic, and for thispurpose electrodes may be inserted by catheters via the venous orarterial system. Catheters are also used to carry laser or RF orultrasound energy to specific sites in the heart or elsewhere in thecirculatory system, in order to ablate tissue for therapeutic purposes.All of these invasive procedures involve obvious risks and expenses.

Ultrasound energy from external transducer arrays has been focused ontumors in order to destroy them by heating.

SUMMARY OF INVENTION

An aspect of some embodiments of the invention relates to stimulatingcardiac tissue, or any other excitable tissue such as muscles andnerves, using ultrasound, for diagnostic and/or therapeutic purposes,using transducers located outside the body, or in the esophagus or othernon-invasive body channels, such as the nasal cavities. Optionally,ultrasound contrast agents, for example microbubbles or liposomes, areused to enhance the procedure, for example by increasing the sensitivityof the cardiac tissue to stimulation.

In some embodiments of the invention, an imaging system is used to trackand observe the heart before, during, and/or after the cardiac tissue isstimulated. This is done, for example, in order to observe the local orglobal mechanical response of the heart to the stimulation, or to focusthe ultrasound energy on the correct spot. Optionally, the imagingsystem is an ultrasound imaging system, using the same transducers asare used for stimulation. Alternatively or additionally, otherultrasound transducers may be used for imaging. Alternatively oradditionally, a Computer Aided Tomography system using x-rays, aMagnetic Resonance Imaging system, or any imaging system known to theart may be used. Optionally, contrast agents are used to improve imagequality, and/or to distinguish between perfused and non-perfused tissue.

In some embodiments of the invention, the location and orientation ofthe heart, or a particular point on the heart, are tracked in real timewhile ultrasound is used to stimulate the heart. Such tracking makes itpossible to repeatedly focus ultrasound on the same spot in the heart,or to successively focus ultrasound on two or more spots with knownrelative positions.

In some embodiments of the invention, ultrasound waves are focused onone small spot in the heart, to stimulate the tissue, and the responseto stimulation is observed. This stimulation spot can be deep inside themyocardium, as well as on the exterior or interior surface of the heart.Optionally, after a period of time, the ultrasound waves are focused ona different stimulation spot. Alternatively or additionally, theultrasound waves are focused on more than one stimulation spotsimultaneously, or nearly simultaneously relative to the speed ofpropagation of signals in the heart. For each stimulation spot or set ofstimulation spots, measurements are optionally made of the intensity andduration of ultrasound needed to induce action potentials, eitherpropagating or non-propagating, and the spatial distribution of thepotential is optionally measured, as a function of time. The mechanicalresponse of tissue to action potentials is optionally measured as afunction of time, for example by observing changes in thickness andmotion of the cardiac wall, at the stimulation spot and at other spots.

In an exemplary embodiment of the invention, the following configurationis used. The ultrasound source is aimed at a particular location in theheart and its firing is synchronized to the cardiac cycle, for example,using an ECG (which may provide local electrical information) or usingan analysis of a series of images. The analysis may be automatic ormanual, for example. The imager is also aimed at the particular locationand/or at a location where an effect of the excitation is expectedand/or is desired to be studied. Optionally, the imager is closelysynchronized with the stimulating ultrasound, which may make it easierto detect the short-term mechanical response of the heart tissue to theultrasound. It may also be possible to detect the motion of the heartwall due to the pressure of the ultrasound. In operation, the imager candetect the exact location of excitation (even if the aiming is notprecise), for example, by detecting non-linear effects at the location.In addition, the imager can capture a development of mechanical responseto the excitation, over a period of time, due to the action potential.Further, this detected response may be synchronized with a measurementof electrical activity from outside the body (e.g., using a highresolution ECG) or from inside the body (e.g., using a catheter). Itshould be noted that in this manner a map having a resolution betterthan the aiming ability can be created, by marking the map with theactual excitation signal location. In any case, the analysis of thedetected response and the ECG may be manual or automatic. For example,the mechanical response to the action potential is found automaticallyby using image analysis software to measure changes in wall thickness.When this measurement is synchronized to a local ECG, a delay inmechanical response is calculated.

The results of these measurements are optionally used for identifyingischemic tissue that is permanently damaged, and distinguishing it fromtissue that is stunned or hibernating but could be revived. Tissue thatis overly sensitive to stimulation, and could give rise to arrhythmias,may also be identified. Maps of the location of healthy and pathologicaltissue in the heart are used in some embodiments of the invention todesign spatial and temporal sequences of stimulation that are optimalfor pacemaking. Optionally, such sequences are tested and compared usingultrasound stimulation. Optionally, some tissue is ablated byultrasound, or by other means as known in the art.

In some embodiments of the invention, ultrasound is used to increasemembrane permeability at particular locations in the heart and/orparticular times in the cardiac cycle, in order to selectively increasethe absorption or effect of drugs at those locations and/or times.Optionally, the drugs are delivered to specific locations by a cardiaccatheter.

In some embodiments of the invention, a phased array of transducers isused to generate the focused ultrasound pulses. Alternatively oradditionally, a single transducer with focusing is used. Optionally, thetransducers are placed on the outside of the chest. To avoid having theultrasound energy blocked by the ribs, the transducers optionally areplaced between the ribs. Additionally or alternatively, the transducersare placed on the sternum, or below the rib cage. Additionally oralternatively, the transducers are placed non-invasively inside thebody, for example in the esophagus.

In some embodiments of the invention, ultrasound pulses are used toprovide temporary pacing of the heart, for example when a conventionalpacemaker is temporarily not operating, or during bradycardia.Optionally, different temporal and spatial sequences of ultrasoundpulses are tested and compared, in order to find the best sequence touse for pacing. The different sequences are evaluated using, forexample, electrocardiograph data, systolic pressure measurements, and/orimages showing the mechanical response of the heart, including systolicand diastolic left ventricular volume and ejection fraction.

In some embodiments of the invention, a cardiac catheter is used toprovide direct electrical simulation of the heart, in addition to thestimulation by ultrasound. Direct electrical stimulation may help toidentify tissue pathologies by comparing its effects to the effects ofmechanical stimulation by ultrasound. In one example, such a comparisonis used to distinguish stunned from hibernating myocardium. In anotherexample, the ultrasound pulses are focused at a coarse resolution, andused to produce a coarse map of pathological tissue, and a cardiaccatheter is used to map certain regions more precisely. The imagingsystem is optionally used to determine the precise location of thecardiac catheter. In addition to or instead of electrically stimulatingthe heart, the catheter optionally is used to ablate or otherwise killcardiac tissue, optionally monitoring the process with the imagingsystem. This killing is done by any means known to the art. For examplethe catheter brings electric power to an ohmic or inductive heatingelement, a refrigerating element, an ultrasound transducer or a radiofrequency transmitter in the circulatory system, or the catheter carrieslaser light on a fiber optic cable, or carries a drug.

There is thus provided, in accordance with an embodiment of theinvention, an ultrasound cardiac stimulation system comprising:

a spatially selective ultrasound source comprising at least oneultrasound transducer located outside the circulatory system; and

a controller;

wherein the controller generates an electrical response in the heart bydirecting the ultrasound source to transmit a high enough power level ofultrasound to one or more locations in the heart.

Optionally, there is an injector which injects cardiac drugs into thebloodstream, and the controller changes the rate at which cardiac tissueabsorbs the drugs by directing the ultrasound source to transmit a highenough power level of ultrasound to one or more locations in the heart.

Optionally, the controller is operative to choose the ultrasound powerlevel.

In an embodiment of the invention, the system has sufficient precisionto control the ultrasound power level supplied to cardiac tissue towithin ±20%.

Optionally, the system has sufficient precision to control theultrasound power level supplied to cardiac tissue to within ±10%.

Optionally, the system has sufficient precision to control theultrasound power level supplied to cardiac tissue to within ±3%.

In an embodiment of the invention, an injector which injects one or bothof drugs for treating the heart and contrast agents into thebloodstream.

Optionally, the controller is operative to reduce the power level ofultrasound when the contrast agents are injected.

In an embodiment of the invention, the controller is operative to choosethe one or more locations to which the ultrasound is transmitted.

Optionally, the controller controls the ultrasound source to directultrasound energy to a designated location, and the point of highestpower flux density falls within an axial precision of 3 mm of saiddesignated location.

Alternatively, the axial precision is 1.5 mm.

Optionally, the point of highest power flux density remains within theaxial precision of the designated location for at least 1 millisecond.

Optionally, the point of highest power flux density remains within theaxial precision of the designated location for at least 10 milliseconds.

Optionally, the controller controls the ultrasound source to directultrasound energy to a designated location, and the point of highestpower flux density falls within a transverse precision of 1 mm of saiddesignated location.

Alternatively, the transverse precision is 0.5 mm.

Optionally, the point of highest power flux density remains within thetransverse precision of the designated location for at least 1millisecond.

Optionally, the point of highest power flux density remains within thetransverse precision of the designated location for at least 10milliseconds.

In an embodiment of the invention, the controller controls theultrasound source to direct a high enough power level of ultrasound toone or more locations in the heart to kill cardiac tissue by heating it.

Alternatively or additionally, the controller controls the ultrasoundsource to direct a high enough power level of ultrasound to one or morelocations in the heart to kill cardiac tissue by cavitation.

In an embodiment of the invention, there is an electrocardiograph whichmeasures the timing of the cardiac cycle.

Optionally, the electrocardiograph is operative to distinguish theelectrical response to the ultrasound, originating in any one chamber ofthe heart, from the electrical response originating in any other chamberof the heart.

Optionally, the electrocardiograph is operative to distinguish theelectrical response to the ultrasound, originating in one side of anychamber of the heart, from the electrical response originating in theother side of said chamber of the heart.

Optionally, the electrocardiograph is operative to distinguish theelectrical response to the ultrasound, originating at any location inthe heart, from the electrical response originating one centimeter awayfrom said location.

Optionally, the electrocardiograph is operative to distinguish theelectrical response to the ultrasound, originating at any location inthe heart, from the electrical response originating one millimeter awayfrom said location.

Optionally, the system uses feedback from the electrocardiograph tocontrol the ultrasound power level.

In an embodiment of the invention, the controller is operative to make amap of the heart, showing the ultrasound power flux required to generatethe electrical response at each of several locations in the heart.

Optionally, the controller is operative to direct the ultrasound sourceto transmit a first sequence of timed localized pulses of ultrasoundenergy to the heart, and a second such sequence which differs from thefirst sequence in one or both of timing and location of the pulses, andthe controller is operative to collect a first data set showing theeffects of the first sequence on the heart, and a second data setshowing the effects of the second sequence on the heart.

Optionally, the first data set and the second data set comprise datafrom the electrocardiogram.

Optionally, there is a memory which is operative to store the first dataset and the second data set, a data analyzer which is operative toanalyze data and produce analysis results from the first data set andthe second data set, and a display which displays the analysis results.

Optionally, the first data set and the second data set comprise data onsystolic pressure.

Optionally, the first sequence and the second sequence differ in timingof the pulses.

Alternatively or additionally, the first sequence and the secondsequence differ in location of the pulses.

In an embodiment of the invention, there is a cardiac imaging systemwhich produces images showing the position of one or more locations onthe heart.

Optionally, the first data set and the second data set comprise datafrom the cardiac imaging system.

Optionally, there is an image analyzer which analyzes images produced bythe cardiac imaging system for the first sequence and the secondsequence, and calculates one or more of the systolic left ventricularvolume for the first and second sequence, the diastolic left ventricularvolume for the first and second sequence, and the ejection fraction forthe first and second sequence.

Optionally, the images produced by the imaging system show themechanical response of the heart to stimulation produced by theultrasound.

Optionally, the imaging system is in a fixed position and orientationwith respect to the ultrasound source.

Alternatively or additionally, there are sensors which determine therelative position and orientation of the imaging system and theultrasound source.

Alternatively or additionally, the imaging system determines therelative position and orientation of the ultrasound source by imagingit.

Optionally, the controller coordinates the timing of the imaging systemwith the timing of the ultrasound source.

Optionally, the controller is operative to make a map of the heart,using data from the imaging system, showing the mechanical response ofthe heart at one or more locations to ultrasound energy transmitted toone or more locations.

Optionally, the system uses feedback from the imaging system to controlthe ultrasound power level.

Optionally, the imaging system uses ultrasound imaging.

Optionally, the imaging system shares one or more ultrasound transducerswith the ultrasound source used to generate the electric response in theheart.

Alternatively, the imaging system does not share any ultrasoundtransducers with the ultrasound source used to generate the electricresponse in the heart.

Alternatively or additionally, the imaging system comprises acomputerized tomography x-ray imaging system.

Alternatively or additionally, the imaging system comprises a magneticresonance imaging system.

Optionally, there is image processing software which analyzes the imagesto determine the position of one or more locations on the heart.

Optionally, the image processing software determines the position of oneor more locations on the heart in real time during a cardiac cycle.

Optionally, the controller coordinates the timing of the transmission ofultrasound with the cardiac cycle.

In an embodiment of the invention, there is a cardiac catheter whichgenerates an electrical response in the heart, and a calibration mode ofthe controller, wherein the controller, when it is in the calibrationmode, calibrates the ultrasound power transmitted to the heart by theultrasound array, by comparing a physiological response induced by theultrasound array to a physiological response induced by the catheter.

Optionally, the physiological responses compared by the controllercomprise electrical responses.

Alternatively or additionally, the physiological responses compared bythe controller comprise mechanical responses.

Optionally, the cardiac catheter generates an electrical response bydirect electric stimulation.

Alternatively or additionally, the cardiac catheter comprises aninternal ultrasound transducer, and the cardiac catheter generates anelectrical response by transmitting ultrasound.

In an embodiment of the invention, the cardiac catheter kills cardiactissue.

Optionally, the cardiac catheter comprises a light guide, and the lightguide carries light from the laser, which light kills cardiac tissue.

Optionally, the ultrasound source comprises a phased array of theultrasound transducers.

Optionally, at least one of the at least one ultrasound transducers isadapted for use on the surface of the body.

Optionally, the at least one ultrasound transducers comprise at leasttwo ultrasound transducers, sized and spaced so that they can be placedbetween the ribs, in such a way as to avoid blocking of ultrasound bythe ribs.

Alternatively or additionally, at least one of the at least oneultrasound transducers is adapted for use in the esophagus.

Alternatively or additionally, at least one of the at least oneultrasound transducers is adapted for use in a nasal cavity.

Optionally, the ultrasound source and the controller are operative todirect the ultrasound energy with 90% of the power flux falling within 3mm transversely of the point of highest power flux density.

Alternatively or additionally, the ultrasound source and the controllerare operative to direct the ultrasound energy with 90% of the power fluxfalling within 1.5 mm transversely of the point of highest power fluxdensity.

Alternatively or additionally, the ultrasound source and the controllerare operative to direct the ultrasound energy with 90% of the power fluxfalling within 1 mm transversely of the point of highest power fluxdensity.

Optionally, the ultrasound source and the controller are operative todirect the ultrasound energy with the power flux spreading out to 50% ofits highest density within 6 mm axially of the point of highest powerflux density.

Alternatively or additionally, the ultrasound source and the controllerare operative to direct the ultrasound energy with the power fluxspreading out to 50% of its highest density within 3 mm axially of thepoint of highest power flux density.

Alternatively or additionally, the ultrasound source and the controllerare operative to direct the ultrasound energy with the power fluxspreading out to 50% of its highest density within 1.5 mm axially of thepoint of highest power flux density.

Optionally, the ultrasound source and the controller are operative todirect the ultrasound energy with a power flux density greater than 30watts per square centimeter at the point of highest power flux density.

Alternatively or additionally, the ultrasound source and the controllerare operative to direct the ultrasound energy with a power flux densitygreater than 100 watts per square centimeter at the point of highestpower flux density.

Alternatively or additionally, the ultrasound source and the controllerare operative to direct the ultrasound energy with a power flux densitygreater than 300 watts per square centimeter at the point of highestpower flux density.

Optionally, the ultrasound source and the controller are operative todirect the ultrasound energy in a pulse lasting less than 10milliseconds.

Alternatively or additionally, the ultrasound source and the controllerare operative to direct the ultrasound energy in a pulse lasting lessthan 1 millisecond.

Optionally, the ultrasound source and the controller are operative todirect the ultrasound energy in a pulse lasting for a duration within10% of a duration for which the controller is directed to direct theenergy.

Optionally, the ultrasound source and the controller are operative todirect the ultrasound energy at a frequency greater than 0.5 megahertzand less than 6 megahertz.

There is thus also provided a method of changing a cardiac stimulationsequence for a patient, comprising:

-   -   a) choosing a test sequence of locations in the heart of the        patient, and a time in the cardiac cycle to stimulate each        location;    -   b) stimulating the test sequence of locations at the chosen        times in the cardiac cycle, using an ultrasound cardiac        stimulation system from outside the heart;    -   c) evaluating a change in cardiac synchronization of the patient        associated with the test sequence;    -   d) choosing a stimulation sequence for a pacemaker, based at        least partly on the change in cardiac synchronization that the        test sequence produces; and    -   e) changing a stimulation sequence of the heart to conform to        the chosen stimulation sequence.

In an embodiment of the invention, using an ultrasound cardiacstimulation system from outside the heart comprises using an ultrasoundstimulation system from outside the body.

Optionally, changing a stimulation sequence of the heart comprisesinstalling a pacemaker.

Alternatively or additionally, changing a stimulation sequence of theheart comprises adjusting a pacemaker.

Optionally, adjusting a pacemaker comprises programming a pacemaker.

Optionally, adjusting a pacemaker comprises adjusting a pacemaker toobtain improved cardiac synchronization.

In an embodiment of the invention, (a), (b) and (c) are performed aplurality of times for different test sequences, and choosing an optimalstimulation sequence is based at least partly on the change in a measureof cardiac performance that the different test sequences produce.

Optionally, the measure of cardiac performance comprises cardiac output.

Optionally, evaluating the change in the measure of cardiac performancecomprises using systolic pressure measurements.

Alternatively or additionally, evaluating the change in the measure ofcardiac performance comprises using images of a mechanical response ofthe heart to the stimulation.

Optionally, at least one of the test sequences comprises a plurality oflocations with the same chosen time.

Optionally, evaluating the change in cardiac synchronization comprisesusing electrocardiograph data.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments of the invention are described in the followingsections with respect to the drawings. The drawings are generally not toscale. The same or similar reference numbers are used for the same orrelated features on different drawings. Features found in one embodimentcan also be used in other embodiments, even though all features are notshown in all drawings.

FIG. 1 is a schematic cross-sectional view of the chest and heart,showing ultrasound systems used for stimulating the heart, according toan exemplary embodiment of the invention;

FIG. 2 is a flowchart illustrating how a map is made of the sensitivityof the heart to stimulation by ultrasound pulses;

FIG. 3 is a flowchart showing how the imaging system is used to trackthe location of different spots on the heart in real time; and

FIG. 4 is a flowchart showing how cardiac tissue is destroyed, while theeffects are monitored.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

FIG. 1 schematically shows an ultrasound system according to anexemplary embodiment of the invention. A heart 10 is shown in across-section of a patient's chest 12. A phased array 14 of ultrasoundtransducers focuses ultrasound waves 16 on a spot 18 in the wall of theheart, stimulating cardiac tissue at that spot and possibly inducingaction potentials, detected by an electrocardiograph 20. By adjustingthe relative phases and amplitudes of the different transducers in thearray, the ultrasound can generally be focused on any desired spot 18.Alternatively, any other method of focusing ultrasound known to the artis used to focus the ultrasound waves on spot 18. The diameter of thespot cannot be much smaller than one wavelength, assuming that it is inthe far field of the transducers, i.e. at least several wavelengths awayfrom the transducers. If it is desired to focus the ultrasound on aregion much smaller than the thickness of the myocardium, the frequencyof the ultrasound optionally has a frequency approximately 1 MHz orhigher, which would have a wavelength in the body of about 1.5 mm orless. Ultrasound transducers exist which can operate at frequencies ashigh as 10 MHz. If the frequency is too high, however, and the desiredfocused spot is not close enough to the transducers, then the ultrasoundwill be largely absorbed before reaching the desired spot, and highertransducer power or more transducers will be needed to produce the sameultrasound power flux at the spot. Typically, frequencies between 0.5and 6 MHz are used, and the focused spot is elliptical, 1 to 2 mm indiameter and 4 to 6 mm in length in the direction of propagation, withthe acoustic pressure outside the spot significantly lower than the peakpressure. Focused spots with dimensions greater or smaller than thesevalues, for example 0.5 mm to 4 mm in diameter and 2 mm to 10 mm inlength, are also optionally used. Peak acoustic pressures are typically2 to 4 MPa, corresponding to powers of 125 to 500 watts per squarecentimeter, and pulse lengths are typically 1 to 10 milliseconds long.However, optionally ultrasound pulses with frequencies, powers and pulselengths of 1 to 5 MPa, corresponding to 30 to 800 watts per squarecentimeter, or even greater than or less than this range, are used.

Transducer array 14 is shown outside the chest in FIG. 1. To avoid theproblem of ultrasound waves reflecting from the ribs, which have a verydifferent acoustic impedance than the soft parts of the body, thetransducers are optionally placed between the ribs, or below the ribcage. Alternatively, they are placed inside the chest, in the esophagus.

An imaging system 22 is used to determine the position and orientationof the heart, relative to transducer array 14, so that ultrasound energycan be accurately focused on a desired spot on the heart by transducerarray 14. Although FIG. 1 shows an imaging system that is separate fromtransducer array 14, optionally transducer array 14 is used for anultrasound imaging system, as well as for stimulating cardiac tissue. Inthis case, ultrasound waves for imaging purposes are optionallytransmitted alternately with ultrasound waves for cardiac stimulation.If the imaging waves and stimulating waves are transmitted close enoughtogether in time, then the heart will not move very much, and theinformation from the imaging system can still be used to accuratelyfocus the stimulating waves. Alternatively or additionally, thestimulating waves themselves are used for imaging. The imaging systemneed not be an ultrasound imaging system. It could be an x-ray CATsystem, or an MRI system, or any other medical imaging system known tothe art.

If imaging system 22 is not an ultrasound imaging system using the sametransducer array 14 that is used for stimulation, then it may bedesirable to know the relative position and orientation of imagingsystem 22 and transducer array 14. Ultrasound can then be used tostimulate a spot whose position is defined by imaging system 22, andimaging system 22 can image a spot that has been stimulated, observingthe effects of the stimulation. Optionally, transducer array 14 isrigidly connected to imaging system 22, so that they always have thesame relative position and orientation. Alternatively, there are sensorsmounted on transducer array 14, imaging system 22, or both of them,which sense the relative position and orientation of transducer array 14and imaging system 22. Alternatively, imaging system 22 determines therelative position and orientation of transducer array 14 by imaginingit. This option is especially useful when transducer array 14 is in theesophagus.

A computer 24 controls the phase, amplitude, and timing of ultrasoundwaves emitted by the transducers in transducer array 12, using inputfrom the human operator, the imaging system, and the electrocardiograph.Details of how this is done, according to an embodiment of theinvention, are given in FIG. 2. Computer 24 could comprise an generalpurpose computer running appropriate software, or custom-designedcontrol circuitry, or a combination of the two.

FIG. 1 schematically shows an intravenous tube 26, which is used tointroduce contrast agents into the bloodstream, during ultrasoundstimulation. Contrast agents, which are encapsulated small gas bubbles,significantly attenuate the propagating ultrasound energy, reflecting,scattering and absorbing it. The contrast agent bubbles oscillate andsometimes burst, producing extremely high pressures locally. Thisenhances the stimulating effect of ultrasound on cardiac tissue. As aresult, lower power transducers can be used to produce the samestimulation effect, and there may be less heating of tissue for the samestimulation effect. Contrast agents are also useful in imaging, forexample for showing the precise boundaries of tissue with normalperfusion of blood and regions with reduced or no perfusion.

Alternatively or additionally, intravenous tube 26 is used to introducedrugs into the bloodstream during ultrasound stimulation of the heart.Since ultrasound stimulation can increase the permeability of cellmembranes, certain locations in the heart will be induced to take updrugs from the bloodstream, more than other regions that are notstimulated. The uptake of drugs can also be timed to occur at certaintimes in the cardiac cycle, if the ultrasound stimulation is gated withan electrocardiograph. Alternatively or additionally, the contrastagents and/or the drugs can be introduced into the heart by a cardiaccatheter, rather than intravenously, allowing additional control overthe spatial and temporal distribution of the contrast agents and/ordrugs.

FIG. 2 is a flowchart showing how the transducer array is used to mapregions of healthy and pathological tissue in the heart, according to anexemplary embodiment of the invention. Tissue is optionally classifiedas healthy or pathological according to one or more of several criteria,for example:

-   -   Ultrasound power level required to induce an action potential    -   Time delay after ultrasound energy is applied, before action        potential appears    -   Refractory period after action potential is induced, before        another action potential can be induced    -   Magnitude and delay of mechanical response to action potential    -   Amplitude and duration of action potential        The flowchart in FIG. 2 illustrates only how the first        criterion, ultrasound power level required to induce an action        potential, is mapped, but optionally any one or combination of        these criteria are used to make a map. Using only the first        criterion, the map identifies regions which are more susceptible        than normal, or less susceptible than normal, to producing extra        action potentials (beyond those associated with the regular        heartbeat) when stimulated by ultrasound. Such a map can reveal        the location of ischemic tissue, which typically requires higher        than normal ultrasound levels to produce an action potential,        and/or tissue which is susceptible to arrhythmias, which may        require a lower than normal ultrasound level to produce an        action potential.

The steps shown in the flowchart in FIG. 2 are optionally performed by acontroller, for example a computer with an interface to the humanoperator. At 100, the initial step in the flowchart, a region is chosenfor mapping, either the whole heart or a part of the heart, and therange of ultrasound power levels is optionally chosen. This range startsat a level well below the power that would be needed to induce an actionpotential in normal tissue, and ends at a level above the power thatwould be needed to induce an action potential in normal tissue, butoptionally not at such a high level that the tissue could be damaged byheating or cavitation. The region for mapping is optionally chosen bythe operator as a range of myocardial coordinates, defined in relationto the heart tissue, i.e. a given point on the heart has constantmyocardial coordinates even while its absolute position is changingbecause the heart is beating. Alternatively, the range could be chosenby the operator by dragging a mouse across a 3-D displayed image of theheart (for example, a series of 2-D cross-sections) frozen at aparticular phase in the cardiac cycle. Optionally, in addition tochoosing a range of positions and powers, a phase in the cardiac cycle,or a set of phases, is also chosen for mapping. The response of tissueto stimulation generally depends on the phase in the cardiac cycle atwhich the stimulation is applied. Optionally, instead of setting therange of positions, powers, and phase initially, they are chosen orchanged during the procedure.

In 102 and 104, the myocardial coordinates of the spot to be stimulatedare set at the first point on the grid to be mapped, and the power isset at the bottom of the range. In 105, the controller waits for thedesired phase in the cardiac cycle, using electrocardiograph data, forexample, to determine at what time the desired phase occurs. In 106, aquick image, which need not have high resolution, is made of the heart,in order to locate the absolute position (relative to the transducers)of the spot to be stimulated. Making an error in location of the focusedspot is potentially dangerous, since a high power ultrasound pulseintended for an insensitive spot could be focused by mistake on a verysensitive area and induce fibrillation. In 108 and 110, the image madein 106 is used to determine the orientation and location of the heart,and this information is used to convert the myocardial coordinates ofthe point being stimulated to thoracic coordinates, defined relative tothe chest cavity (and hence to the transducers, which are optionallypressed against the outside of the chest). Some details of how thiscalculation is done are given below in the description of FIG. 3. If theimaging and calculation could be done in less than 50 milliseconds, orbetter yet in less than 10 milliseconds, then the heart would move verylittle between the time it is imaged and the time the ultrasound energyis applied for stimulation. Alternatively, instead of performing 106,108 and 110, the range of points to be mapped is directly defined interms of thoracic coordinates at a particular phase in the cardiaccycle, and the ultrasound energy is always applied at the same phase inthe cycle. A disadvantage of this alternative method is that there couldbe variations in position and orientation of the heart from oneheartbeat to the next.

If the ultrasound transducers are located in the esophagus rather thanon the outside of the chest, then it may not be sufficient just todefine the position of the point to be mapped in thoracic coordinates.In addition, it may be necessary to take into account changes inposition of the transducers relative to the chest cavity. Optionallythis is done by using an external imaging system to locate the positionof the stimulating transducers in the esophagus. Alternatively, if thesame transducers are used for stimulation and imaging, then thosetransducers can be used directly to find the location of the heart (orof the desired point on the heart) relative to the transducers.

In 112, the stimulating ultrasound energy is focused on the desired spoton the heart. As described above in the description of FIG. 1, this isoptionally done by first using a computer to calculate the phases andamplitudes of the transducers in the array, needed to focus ultrasoundenergy on the desired spot. In 114, a cine (moving) image is optionallymade of the heart, in order to assess the mechanical response of theheart, if any, to the stimulation. Optionally, instead of storing theentire cine image, the image is processed to track only a limited set ofpoints on the heart, sufficient to characterize the mechanical responseof the heart, and only these results are stored. If the imaging systemdoes not use the transducers used for stimulation, then the cine imagingoptionally begins before the stimulation is applied, and continues whilethe stimulation is applied and for a given period afterwards. Even ifthe same transducers are used for imaging and stimulation, the cineimaging optionally begins before the stimulation, and is brieflyinterrupted while the transducers are used for stimulation, and resumedafterwards. Optionally the cine image or a still image is preciselysynchronized with the ultrasound stimulation, and is used to detect theshort-term mechanical response of the heart tissue to the ultrasoundstimulation, which may provide more information about the exact locationof the ultrasound stimulation.

At 116, the controller examines data, for example from anelectrocardiograph, to determine whether the ultrasound stimulationinduced an action potential, beyond the action potential that alreadyexisted as part of the natural cardiac cycle. The electrocardiographprovides some information about the spatial distribution of actionpotentials, as well as their amplitude and time dependence. Optionally,the electrocardiograph is calibrated before it is used to measureinduced action potentials, for example by comparing the induced actionpotentials to the regular action potential. If no extra action potentialis observed, and if the power level is not yet at the top of the chosenrange (118), then the power is raised to the next level (120), and theflow goes back to 105, in preparation for a new application ofultrasound energy at the same spot. If the power was already at themaximum level, then this spot is recorded as unresponsive (124), and theflow goes to 132.

Optionally, instead of starting at the lowest power level and increasingthe power one step at a time, the power starts at the middle of therange, at a level that has a 50% chance of exciting an action potential,according to some model. If an action potential is seen, then the poweris lowered to a level that now has a 50% chance of eliciting an actionpotential, taking into account the previous results. If an actionpotential is not seen, then the power is raised to a level that now hasa 50% chance of eliciting an action potential, taking into account theprevious results. This procedure is continued until the exact thresholdfor eliciting an action potential is found, to the desired precision.This “zeroing in” procedure has an advantage over the “one step at atime” procedure, in that the number of steps required scales as thelogarithm of the desired precision, rather than scaling linearly withthe desired precision. A disadvantage of the “zeroing in” procedure isthat it might overstimulate a very sensitive spot, causing fibrillation.Many other procedures are possible for determining the threshold foreliciting action potentials, which will be apparent to persons skilledin the art.

If an extra action potential was seen, then the data is examined to seewhether the action potential is propagating, and how it propagates(126). This information is recorded (128), and (130) any mechanicalresponse is assessed (based on the cine image made in 114, for example),and recorded. Optionally, image processing software is used to assignone or more quantitative values to characterize the mechanical response.Alternatively or additionally, the mechanical response could becharacterized by the operator after viewing the cine image.Alternatively or additionally, the cine image for each spot is stored,and the mechanical response is evaluated at leisure after the map ofaction potential threshold is completed.

At 132, if all spots in the grid have not been examined, then (134) themyocardial coordinates are set for the next spot in the grid, and theflow goes back to 104. Once all spots in the grid have been examined,the procedure ends (136). The recorded data on the ultrasound powerthreshold needed to induce an action potential at each point, and on thepropagation of induced action potentials, are then used to create one ormore maps, for example using post-processing software. The maps couldshow the propagation paths, as well as the action potential threshold ateach spot. The accuracy of the map showing action potential thresholdswill be confirmed if it is consistent with the map of propagation paths,for example if it shows that regions that are resistant to inducingaction potentials are also regions that block propagation of actionpotentials induced elsewhere.

Although the flowchart in FIG. 2 assumes that ultrasound stimulation isonly applied at one phase in the cardiac cycle, optionally a map couldbe made for each of several phases. For example, instead of ending theprocedure at 136, the controller could change the phase and loop back to102, until all desired phases were examined. Alternatively, the phasecould be changed in an inner loop. For example, at each power level, foreach spot, ultrasound stimulation could be done at each of severaldifferent phases. Optionally, once an action potential is observed, thecontroller moves to the next spot. This procedure produces a map of theminimum power needed to induce an action potential at the most sensitivephase in the cardiac cycle. Alternatively, the power threshold forinducing an action potential is measured for each of several phases ateach spot.

In making the map, corrections to the ultrasound power level areoptionally made taking into account absorption of ultrasound energybetween the transducers and the focused spot. The amount of absorptionmay be estimated by using known values for absorption lengths ofultrasound at the frequency used, in different types of tissue.Alternatively or additionally, absorption may be measured by using datafrom the imaging system, if it is an ultrasound imaging system, or bydetecting stimulating ultrasound waves reflected back to thetransducers. For example, images can be compared at lower ultrasoundfrequency, where there is less absorption, and higher frequency wherethere is more absorption, in order to calibrate the amount of absorptionat the frequency used for stimulation. In some embodiments of theinvention, the ultrasound power flux focused on a given spot in theheart is controlled to within 10%, taking into account errors in thepowers and phases of the transducers, and uncertainties in the amount ofpower that is absorbed between the transducers and the focused spot.Alternatively, the power is controlled only to within 20%, or to withinbetter than 3%.

Corrections are also optionally made to the map by taking into accountthe finite amplitude of ultrasound at locations other than the focusedspot, which can be calculated from the size, spacing, and number oftransducers in the array, and by modeling reflections and refraction ofultrasound waves. Such a spatial distribution of the ultrasoundintensity could stimulate action potentials first at those otherlocations, if the tissue there is much more sensitive than the tissue atthe focused spot. One way to calculate these corrections is to make amap of sensitivity initially ignoring these effects, and then seeingwhether such effects would be important according to that map, andcorrecting for them, and making a new map. This procedure is repeateduntil the map changes very little from one iteration to the next.Alternatively or additionally, information about the intensity ofultrasound energy at different locations is obtained by measuring theamplitude of higher harmonics (integer multiples of the transmittedfrequency) generated at those locations.

Optionally, data on the induced action potentials from theelectrocardiograph, and/or imaging data on the mechanical response toultrasound stimulation, are used to control the power level of theultrasound transducers using feedback in real time, instead of or inaddition to using this data to make corrections to the appliedultrasound power when analyzing the data afterwards.

FIG. 3 is a flowchart showing how the controller analyzes the data fromthe imaging system and calculates the location (relative to thetransducers) of the spot on the heart where the ultrasound energy is tobe focused, according to an embodiment of the invention. This is done,for example, using the following steps. At 200, a 3D image of the heartis recorded, using the imaging system. At 202, image analysis softwareis used to locate in the image key landmarks on the heart, for examplethe centers of valves, certain branching points of the coronary artery,certain points at the edge of the septum, etc. At 204, the coordinates(relative to the imaging system) of the landmarks are used to calculatethe values of a finite set of parameters which substantiallycharacterize the mechanical state of the heart. For example, theparameters comprise three parameters representing the 3D position of thecenter of the heart, three parameters representing the orientation ofthe heart in space, and four parameters describing the state ofexpansion of each chamber of the heart. At 206, the values of theparameters are used to calculate the thoracic coordinates of the desiredspot, whose location is defined in myocardial coordinates, according toa algorithm worked out in advance. The algorithm is based on amathematical model of where each point on the heart is located as afunction of the different parameters, for example the state of expansionof each chamber. This coordinate transformation algorithm can beverified for human hearts in general, and perhaps some free parametersare calibrated for individual patients. This verification andcalibration is done by locating spots on the heart (other than thelandmarks) on the image, and seeing whether their location is correctlypredicted by the algorithm.

Other procedures may be used to accomplish the same result. For example,instead of only locating a small set of landmarks on the image, theimage processing software determines the location (relative to theimaging system) of each point in a 3D grid of points defined inmyocardial coordinates, and interpolation is then used to find thelocation of the spot. In effect this procedure would use a much largerset of parameters, but a much simpler coordinate conversion algorithm,than the procedure outlined above.

Once the coordinates of the spot are known, the controller calculatesthe ultrasound wave phases and amplitudes of the transducers in thearray required to direct the ultrasound energy to the spot.

Once a map has been made of the sensitivity of the cardiac tissue tostimulation, or of other properties such as delay time of actionpotentials or refractory time, the information is optionally used todevelop and optimize sequences of cardiac stimulation for pacemaking.Selected spatial and temporal sequences of stimulation are tested ormodeled, using ultrasound pulses focused on the desired locations, atthe desired times in the cardiac cycle, as determined by theelectrocardiograph. Optionally, more than one location is stimulated atnearly the same instant. Optionally, the electrocardiograph, and/or theimaging system, is used to measure the strength and regularity of theheartbeat, to assess the efficacy of a given sequence for pacemaking,and the sequence is compared to other sequences. Additionally oralternatively, one or more other indices are used to evaluate a givensequence, including, for example, systolic pressure, systolic leftventricular volume, diastolic left ventricular volume, and/or ejectionfraction. (These indices are optionally measured by any conventionalmeans, including the use of images or other data from the ultrasonic, orother, imaging system. Optionally, image analysis is used to calculateone or more of these indices from the images. Alternatively oradditionally, the indices are determined by a person viewing theimages.) Once an effective sequence is found, a pacemaker using directelectrical stimulation can be programmed and implanted to produce themost effective stimulation sequence.

The ultrasound system used for stimulating cardiac tissue can also beused to destroy cardiac tissue, for example diseased or arrhythmogenictissue. FIG. 4 is a flowchart showing the procedure by which tissue isdestroyed, according to an exemplary embodiment of the invention.Initially, at 300, the ultrasound power level, coordinates of the firstspot, and phase in the cardiac cycle are chosen. Although it is possibleto track the spot continuously as the heart beats, and to keepultrasound focused on it throughout the cardiac cycle, there areadvantages to applying ultrasound power for a time short compared to thecardiac period, and to repeat this at the same phase of the cardiaccycle over several heartbeats if necessary. One advantage is that theremay be less error in aiming the ultrasound, since the location of thespot relative to the chest does not vary by that much from one cardiaccycle to the next, at the same phase. Another advantage is that theultrasound power can be applied to the spot at a phase in the cardiaccycle when the surrounding cardiac tissue is not sensitive tostimulation by ultrasound. In 302, the controller waits for the rightphase in the cardiac cycle. Then (304) the heart is imaged, and, asoutlined in FIG. 3, the image is used to convert the myocardialcoordinates of the chosen spot to thoracic coordinates (306). In 308 apulse of ultrasound energy is transmitted. The power and duration of thepulse are optionally chosen so that it destroys a small amount oftissue, but not enough to do serious damage to the heart if the energywas not focused in exactly the right spot. In 310, the heart is imagedagain, and the image is examined (312) to verify the destruction oftissue at the intended spot. In addition (314), an ultrasoundstimulation sequence is optionally performed to verify that thedestruction of tissue at that spot has the expected effect on electricalpropagation paths. One well known reason for destroying cardiac tissue,possibly even healthy tissue, is to prevent propagation of actionpotentials on undesired paths. If the imaging and stimulation testreveal that the goal was accomplished (316), the procedure ends (318).If the imaging and/or stimulation test reveal that the ultrasound energywas not aimed correctly (320), or if the power was too high or too low,then appropriate adjustments are made (322), and the procedure returnsto 302 to prepare for transmitting another pulse of ultrasound. If theimaging and/or stimulation test reveal that everything is proceeding asplanned (320), but that more tissue needs to be destroyed at the samespot (324), then the procedure also returns to 302. If the procedure isproceeding as planned but the work on that spot is done, then the nextspot is chosen, and the power level may be adjusted (322), and theprocedure returns to 302.

Optionally, tissue is destroyed by heating it, which can kill it orcause it to disintegrate. Alternatively or additionally, tissue iskilled by cavitation induced by ultrasound. In either case, the tissueis killed directly, for example by ablating it, or indirectly, forexample by inducing apoptosis. Optionally, ultrasound contrast agent isused to increase cavitation effects and/or energy absorption at the siteof tissue being killed.

Instead of or in addition to using ultrasound energy from externaltransducers to kill cardiac tissue, ultrasound stimulation can be usedto monitor the killing of cardiac tissue by other means known to theart, such as laser light, radio waves, or ultrasound waves brought tothe heart by a cardiac catheter. The words “kill” and “destroy” andtheir conjugates, as used herein, mean “kill directly or indirectly,”and includes, for example, ablation and inducing apoptosis.

The words “locations on the heart” as used herein mean locations on thesurface of the heart or inside the heart, including within themyocardium. The terms “position” and “orientation” when used herein withreference to an imaging system, mean position and orientation of theelements of the imaging system whose position and orientation affect thepoint of view of the images produced by the imaging system. The terms“data analyzer” and “image analyzer” as used herein mean any devicewhich analyzes data, including software running on a general purposecomputer, and specially designed digital or analog electronic circuits,whether or not it analyzes data in real time, and whether or not it islocated in the vicinity or located remotely. The term “analysis results”produced by a data analyzer from a data set can include a selection ofany or all unchanged pieces of data in the data set, as well as theresults of mathematical calculations using the pieces of data in thedata set. The words “comprise” and “include” and their conjugates asused herein mean “include but are not necessarily limited to.” While theinvention has been described with reference to certain exemplaryembodiments, various modifications will be readily apparent to and maybe readily accomplished by persons skilled in the art without departingfrom the spirit and scope of the above teachings.

1. An ultrasound cardiac stimulation system comprising: a spatiallyselective ultrasound source comprising at least one ultrasoundtransducer located outside a circulatory system of a body; and acontroller; wherein the controller generates an electrical response in aheart by directing the ultrasound source to transmit a pulse or pulsesof ultrasound to one or more locations in the heart on a periodic basissuitable for cardiac pacing, wherein said of ultrasound pulse or pulsesare configured to include a rower level and duration suitable to inducean action potential in the heart.
 2. A system according to claim 1 andincluding an injector which injects cardiac drugs into the bloodstream,wherein the controller changes a rate at which cardiac tissue absorbsthe drugs by directing the ultrasound source to transmit a high enoughpower level of ultrasound to one or more locations in the heart.
 3. Asystem according to claim 1, wherein the controller is operative tochoose the ultrasound power level.
 4. A system according to claim 3,wherein the system has sufficient precision to control the ultrasoundpower level supplied to cardiac tissue to within ±10%.
 5. A systemaccording to claim 4, wherein the system has sufficient precision tocontrol the ultrasound power level supplied to cardiac tissue to within±3%.
 6. A system according to claim 3, and including an injector whichinjects one or both of drugs for treating the heart and contrast agentsinto the bloodstream.
 7. A system according to claim 6 wherein theinjector injects drugs into the bloodstream, and the controller isfurther configured to change the rate at which cardiac tissue absorbsthe drugs by directing the ultrasound source to transmit a high enoughpower level of ultrasound to one or more locations in the heart.
 8. Asystem according to claim 1, wherein the controller is operative tochoose the one or more locations to which the ultrasound is transmitted.9. A system according to claim 8, wherein the controller controls theultrasound source to direct ultrasound energy to a designated location,and a point of highest power flux density falls within an axialprecision of 3 mm of said designated location.
 10. A system according toclaim 9, wherein the point of highest power flux density remains withinthe axial precision of the designated location for at least 1millisecond.
 11. A system according to claim 8, wherein the controllercontrols the ultrasound source to direct ultrasound energy to adesignated location, and the point of highest power flux density fallswithin a transverse precision of 1 mm of said designated location.
 12. Asystem according to claim 11, wherein the point of highest power fluxdensity remains within the transverse precision of the designatedlocation for at least 1 millisecond.
 13. A system according to claim 8,wherein the controller additionally controls the ultrasound source todirect a high enough power level of ultrasound to one or more locationsin the heart to kill cardiac tissue by heating.
 14. A system accordingto claim 8, wherein the controller additionally controls the ultrasoundsource to direct a high enough power level of ultrasound to one or morelocations in the heart to kill cardiac tissue by cavitation.
 15. Asystem according to claim 1, and including an electrocardiograph whichmeasures the timing of the cardiac cycle.
 16. A system according toclaim 15, wherein the electrocardiograph is operative to distinguish theelectrical response to the ultrasound, originating at any location inthe heart, from the electrical response originating one centimeter awayfrom said location.
 17. A system according to claim 15, wherein thecontroller coordinates the timing of the transmission of ultrasound withthe cardiac cycle.
 18. A system according to claim 17, wherein saidcontroller coordinates said timing with one particular phase in thecardiac cycle.
 19. A system according to claim 17, wherein, saidcontroller coordinates said timing with more than one particular phasein the cardiac cycle.
 20. A system according to claim 15, and includinga cardiac catheter which generates an electrical response in the heart,and a calibration mode of the controller, wherein the controller, whenin the calibration mode, calibrates the ultrasound power transmitted tothe heart by the ultrasound array, by comparing a physiological responseinduced by the ultrasound array to a physiological response induced bythe catheter.
 21. A system according to claim 20 wherein thephysiological responses compared by the controller comprise electricalresponses.
 22. A system according to claim 20, wherein the physiologicalresponses compared by the controller comprise mechanical responses. 23.A system according to claim 20, wherein the cardiac catheter generatesan electrical response by direct electric stimulation.
 24. A systemaccording to claim 20, wherein the cardiac catheter comprises aninternal ultrasound transducer, and the cardiac catheter generates anelectrical response by transmitting ultrasound.
 25. A system accordingto claim 20, wherein the cardiac catheter kills cardiac tissue.
 26. Asystem according to claim 25, and including a laser, wherein the cardiaccatheter comprises a light guide, and the light guide carries light fromthe laser, which light kills cardiac tissue.
 27. A system according toclaim 15, wherein the controller uses feedback from theelectrocardiograph to control the ultrasound power level.
 28. A systemaccording to claim 15, wherein the controller is operative to make a mapof the heart, showing the ultrasound power flux required to generate theelectrical response at each of several locations in the heart.
 29. Asystem according to claim 15, wherein the controller is operative todirect the ultrasound source to transmit a first sequence of timedlocalized pulses of ultrasound energy to the heart, and a second suchsequence which differs from the first sequence in one or both of timingand location of the pulses, and the controller is operative to collect afirst data set showing the effects of the first sequence on the heart,and a second data set showing the effects of the second sequence on theheart.
 30. A system according to claim 29, and including a cardiacimaging system, and an image analyzer which analyzes images produced bythe cardiac imaging system for the first sequence and the secondsequence, and calculates one or more of a systolic left ventricularvolume for the first and second sequence, a diastolic left ventricularvolume for the first and second sequence, and an ejection fraction forthe first and second sequence.
 31. A system according to claim 1, andincluding a cardiac imaging system which produces images showing theposition of one or more locations on the heart.
 32. A system accordingto claim 31, and including sensors which determine the relative positionand orientation of the imaging system and the ultrasound source.
 33. Asystem according to claim 31, wherein the imaging system determines therelative position and orientation of the ultrasound source by imaging.34. A system according to claim 31, wherein the controller coordinatesthe timing of the imaging system with the timing of the ultrasoundsource.
 35. A system according to claim 31, wherein the imaging systemuses ultrasound imaging.
 36. A system according to claim 35, wherein theimaging system shares one or more ultrasound transducers with theultrasound source used to generate the electric response in the heart.37. A system according to claim 31, and including image processingsoftware which analyzes the images to determine the position of one ormore locations on the heart.
 38. A system according to claim 37, whereinthe image processing software determines the position of one or morelocations on the heart in real time during a cardiac cycle.
 39. A systemaccording to claim 31 wherein the controller is operative to make a mapof the heart, using data from the imaging system, showing the mechanicalresponse of the heart at one or more locations to ultrasound energytransmitted to one or more locations.
 40. A system according to claim31, wherein the controller uses feedback from the imaging system tocontrol the ultrasound power level.
 41. A system according to claim 31,wherein said cardiac imaging system is configured to be synchronizedwith said ultrasound stimulation, in order to detect short-termmechanical response of heart tissue to the ultrasound stimulation.
 42. Asystem according to claim 1, wherein the ultrasound source comprises aphased array of the ultrasound transducers.
 43. A system according toclaim 1, wherein at least one of the at least one ultrasound transduceris adapted for use on a surface of the body.
 44. A system according toclaim 43, wherein the at least one ultrasound transducer comprises atleast two ultrasound transducers, sized and spaced so as to be placedbetween ribs of the body, in such a way as to avoid blocking ofultrasound by the ribs.
 45. A system according to claim 1, wherein atleast one of the at least one ultrasound transducer is adapted for usein an esophagus of the body.
 46. A system according to claim 1, whereinthe ultrasound source and the controller are operative to direct theultrasound energy with 90% of the power flux falling within 3 mmtransversely of the point of highest power flux density.
 47. A systemaccording to claim 46, wherein the ultrasound source and the controllerare operative to direct the ultrasound energy with 90% of the power fluxfalling within 1 mm transversely of the point of highest power fluxdensity.
 48. A system according to claim 1, wherein the ultrasoundsource and the controller are operative to direct the ultrasound energywith the power flux spreading out to 50% of the highest density thereof,within 6 mm axially of the point of highest power flux density.
 49. Asystem according to claim 48, wherein the ultrasound source and thecontroller are operative to direct the ultrasound energy with the powerflux spreading out to 50% of the highest density thereof, within 1.5 mmaxially of the point of highest power flux density.
 50. A systemaccording to claim 1, wherein the ultrasound source and the controllerare operative to direct the ultrasound energy with a power flux densitygreater than 30 watts per square centimeter at the point of highestpower flux density.
 51. A system according to claim 50, wherein theultrasound source and the controller are operative to direct theultrasound energy with a power flux density greater than 100 watts persquare centimeter at the point of highest power flux density.
 52. Asystem according to claim 51, wherein the ultrasound source and thecontroller are operative to direct the ultrasound energy with a powerflux density greater than 300 watts per square centimeter at the pointof highest power flux density.
 53. A system according to claim 1,wherein the ultrasound source and the controller are operative to directthe ultrasound energy in a pulse lasting less than 10 milliseconds. 54.A system according to claim 53, wherein the ultrasound source and thecontroller are operative to direct the ultrasound energy in a pulselasting less than 1 millisecond.
 55. A system according to claim 1,wherein the ultrasound source and the controller are operative to directthe ultrasound energy in a pulse lasting for a duration within 10% of aduration for which the controller is directed to direct the energy. 56.A system according to claim 1, wherein the ultrasound source and thecontroller are operative to direct the ultrasound energy at a frequencygreater than 0.5 megahertz and less than 6 megahertz.
 57. A systemaccording to claim 45, and further including an imaging systemconfigured to locate the position of the at least one ultrasoundtransducer relative to the chest cavity in the esophagus.
 58. A systemaccording to claim 45, wherein said at least one ultrasound transduceris additionally configured to act as a cardiac imaging system whichproduces images showing the position of one or more locations on theheart.
 59. A system according to claim 1, wherein said controller isconfigured to determine whether said ultrasound stimulation has inducedsaid action potential beyond the action potential that already existedas part of the natural cardiac cycle of the heart.
 60. A systemaccording to claim 59, wherein said controller is configured todetermine the exact threshold for the power level of said ultrasoundsource, whereat said action potential beyond the action potential thatalready existed as part of the natural cardiac cycle of the heart isinduced by said ultrasound stimulation.
 61. A system according to claim60, wherein, if said action potential beyond the action potential thatalready existed as part of the natural cardiac cycle of the heart hasnot been induced by said ultrasound stimulation, said controller isconfigured to raise the power level of said ultrasound source.
 62. Asystem according to claim 60, wherein, if said action potential beyondthe action potential that already existed as part of the natural cardiaccycle of the heart has been induced by said ultrasound stimulation, saidcontroller is configured to lower the power level of said ultrasoundsource.
 63. A method of changing a cardiac stimulation sequence for apatient, comprising: a) choosing a test sequence of locations in theheart of the patient, and a time in the cardiac cycle to stimulate eachlocation; b) stimulating the test sequence of locations at the chosentimes in the cardiac cycle, using an ultrasound cardiac stimulationsystem from outside the heart; c) evaluating a change in cardiacsynchronization of the patient associated with the test sequence; d)choosing a stimulation sequence for a pacemaker, based at least partlyon the change in cardiac synchronization that the test sequenceproduces; and e) changing a stimulation sequence of the heart to conformto the chosen stimulation sequence by modifying operation of thepacemaker.
 64. A method according to claim 63, wherein using anultrasound cardiac stimulation system from outside the heart comprisesusing an ultrasound stimulation system from outside the body.
 65. Amethod according to claim 63, wherein changing a stimulation sequence ofthe heart comprises installing a pacemaker.
 66. A method according toclaim 63, wherein changing a stimulation sequence of the heart comprisesadjusting a pacemaker to obtain improved cardiac synchronization.
 67. Amethod according to claim 63, wherein (a), (b) and (c) are performed aplurality of times for different test sequences, and choosing an optimalstimulation sequence is based at least partly on the change in a measureof cardiac performance that the different test sequences produce.
 68. Amethod according to claim 67, wherein the measure of cardiac performancecomprises cardiac output.
 69. A method according to claim 67, whereinevaluating the change in the measure of cardiac performance comprisesusing systolic pressure measurements.
 70. A method according to claim67, wherein evaluating the change in the measure of cardiac performancecomprises using images of a mechanical response of the heart to thestimulation.
 71. A method according to claim 67, wherein at least one ofthe test sequences comprises a plurality of locations with the samechosen time.
 72. A method according to claim 63, wherein evaluating thechange in cardiac synchronization comprises using electrocardiographdata.
 73. A method according to claim 63, wherein, for each chosenlocation in the heart, said stimulating is performed at chosen times inthe cardiac cycle at one particular phase in the cardiac cycle.
 74. Amethod according to claim 63, wherein, for each location in the heart,said stimulating is performed at chosen times in the cardiac cycle atmore than one particular phase in the cardiac cycle.
 75. A methodaccording to claim 63, wherein said ultrasound cardiac stimulationsystem is configured to direct an ultrasound source to transmit a highenough power level of ultrasound to induce an action potential in theheart.